Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The calcitonin receptor is known to couple to Gs and Gq, activating adenylyl cyclase and phospholipase C, respectively. The observation of pertussis-toxin-sensitive responses to calcitonin suggests that the receptor is capable of coupling to Gi/o as well. However, the calcitonin-dependent activation of adenylyl cyclase in HEK-293 cells that stably express the cloned rabbit calcitonin receptor, as in many other cells that express calcitonin receptors, shows little pertussis toxin sensitivity. Calcitonin treatment of these cells stimulates protein kinase C, which is reported to antagonize the receptor-dependent activation of Gi. The possibility that protein kinase C could be antagonizing Galphai-adenylyl cyclase coupling was tested by examining the effects of protein kinase C inhibitors (chelerythrine chloride and sphingosine) or of chronic treatment with phorbol ester to deplete protein kinase C. All three treatments led to a reduction of calcitonin-induced adenylyl cyclase activity that was reversed by pertussis toxin. Inhibiting or depleting protein kinase C had no effect on the activation of adenylyl cyclase by cholera toxin, indicating that Gs and adenylyl cyclase were not affected by these treatments. Calcitonin treatment of HEK-293 cells, that stably express a myc-tagged rabbit calcitonin receptor, induced the formation of complexes of the receptor and Galphai subunits, confirming that the calcitonin receptor interacts with Gi. Thus, the calcitonin receptor can couple to Gi, but the inhibition of adenylyl cyclase by Galphai is negatively regulated by protein kinase C.
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PMID:Protein kinase C antagonizes pertussis-toxin-sensitive coupling of the calcitonin receptor to adenylyl cyclase. 1023 69

HEF1 is a recently described p130(Cas)-like docking protein that contains one SH3 domain and multiple SH2 binding motifs. In B cells, HEF1 is phosphorylated by a cytoskeleton-dependent mechanism that is triggered by integrin ligation. However, the induction of HEF1 phosphorylation by G protein-coupled receptors has not been reported. We found that HEF1, but not p130(Cas), is tyrosine-phosphorylated following stimulation of the rabbit C1a calcitonin receptor stably expressed in HEK-293 cells. The calcitonin-induced tyrosine phosphorylation of HEF1 increased in a time- and dose-dependent manner. Dibutyryl cAMP and forskolin had little or no effect on HEF1 phosphorylation, and the protein kinase A inhibitor H89 failed to detectably inhibit the response to calcitonin, indicating that the G(s)/cAMP/protein kinase A pathway does not mediate the calcitonin effect. Pertussis toxin, which selectively blocks G(i/o) signaling, also had no effect. Increasing cytosolic Ca(2+) with ionomycin stimulated HEF1 phosphorylation and preventing any calcitonin-induced change in cytosolic calcium by a combination of BAPTA and extracellular EGTA completely blocked the calcitonin-induced tyrosine phosphorylation of HEF1. Phorbol 12-myristate 13-acetate also induced HEF1 tyrosine phosphorylation, and the protein kinase C inhibitor calphostin C completely inhibited both calcitonin- and phorbol 12-myristate 13-acetate-stimulated HEF1 phosphorylation. Calcitonin also induced the tyrosine phosphorylation of paxillin and focal adhesion kinase, and the association of these two proteins with HEF1. Pretreatment with cytochalasin D, which disrupts actin microfilaments, prevented the calcitonin-induced HEF1 and paxillin phosphorylation. In conclusion, the calcitonin-stimulated tyrosine phosphorylation of HEF1 is mediated by calcium- and protein kinase C-dependent mechanisms and requires the integrity of the actin cytoskeleton.
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PMID:Cytoskeleton-dependent tyrosine phosphorylation of the p130(Cas) family member HEF1 downstream of the G protein-coupled calcitonin receptor. Calcitonin induces the association of HEF1, paxillin, and focal adhesion kinase. 1045 89

The biosynthesis of 1alpha, 25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3 is catalyzed by 25-hydroxyvitamin D3 1alpha-hydroxylase (CYP27B1) in renal proximal tubules. It was recently demonstrated that LLC-PK1 cells express CYP27B1 mRNA, which is regulated by intracellular cAMP but not vitamin D3. To clarify the effect of calcitonin on vitamin D3 metabolism in vitro, LLC-PK1 cells were incubated with hormonal factors, and expression of CYP27B1 mRNA was measured by quantitative reverse transcription-PCR. Calcitonin at 100 nmol/L significantly increased CYP27B1 mRNA expression by 24 h (271 +/- 21% of control). Incubation with calcitonin over a range of 1 micromol/L to 1 pmol/L resulted in a concentration-dependent increase in CYP27B1 mRNA levels. It is known that the calcitonin receptor has dual intracellular signaling pathways, via protein kinases A and C. Both 500 micromol/L 8-bromo-cAMP, a protein kinase A activator, and 100 nmol/L phorbol 12-myristate 13-acetate, a protein kinase C activator, increased CYP27B1 mRNA levels at 24 h (207 +/- 54 and 246 +/- 58% of control, respectively). However, calcitonin-induced CYP27B1 mRNA expression was only inhibited by the protein kinase C inhibitors staurosporine and calphostin C. The protein kinase A inhibitors Rp-cAMPS at 10 and 100 micromol/L and H-89 at 10 micromol/L had no effect on the action of calcitonin, in spite of cAMP-activation by calcitonin. The present data suggest that calcitonin upregulates CYP27B1 mRNA expression via the protein kinase C pathway in LLC-PK1 cells.
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PMID:Calcitonin induces 25-hydroxyvitamin D3 1alpha-hydroxylase mRNA expression via protein kinase C pathway in LLC-PK1 cells. 1058 84

Previous studies have shown that calcitonin-like immunoreactive substances are secreted by primary prostate cells. Furthermore, exogenously added calcitonin stimulates proliferation of androgen-responsive LnCaP cells. To examine the possible effect of calcitonin on growth of invasive prostate cancer cells, we tested its effects on proliferation of PC-3M cells. Calcitonin stimulated DNA synthesis of PC-3M cells in a dose-dependent fashion, and also stimulated adenylyl cyclase and protein kinase C activities. To further delineate the role of these signaling cascades in proliferation of PC-3M prostate cancer cells, we selectively activated these pathways by transfecting cDNAs expressing constitutively active forms of either Gsalpha (Gsalpha-QL) or Gqalpha (Gqalpha-QL). cDNAs expressing wild-type forms of G-proteins (Gsalpha-WT and Gqalpha-WT) were used as vehicle controls. Gqalpha-QL transfectants exhibited growth inhibition and terminal differentiation. Those expressing Gsalpha-QL exhibited a dramatic increase in growth rate. Gsalpha-QL transfectants displayed an almost 3-fold increase in [3H]-thymidine incorporation and over a 4-fold increase in growth rate when compared with parental PC-3M cells or those expressing wild-type Gsalpha (Gsalpha-WT). The growth-promoting action of Gsalpha-QL could not be mimicked by either 8-bromo cAMP or forskolin. However, nifedipine, a calcium channel antagonist, potently and selectively inhibited DNA synthesis in Gsalpha-QL transfectants. These results suggest that the growth-promoting actions of Gsalpha on PC-3M cells may be mediated by nifedipine-sensitive proliferative events.
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PMID:Role of stimulatory guanine nucleotide binding protein (GSalpha) in proliferation of PC-3M prostate cancer cells. 1114 19

It has been demonstrated that calcitonin-binding sites are present in a variety of tissue types, including in the pituitary gland. Interleukin-6 (IL-6) is also produced in the pituitary and it regulates the secretion of various hormones. In this study, we examined the expression of the calcitonin receptor and the mechanism of IL-6 production induced by calcitonin in the pituitary folliculo-stellate cell line (TtT/GF). The mRNA of calcitonin receptor subtype C1a, but not that of C1b, was detected by RT-PCR in TtT/GF cells and in the normal mouse pituitary. Calcitonin increased cAMP accumulation and IL-6 production in a concentration-dependent manner in TtT/GF cells. As calcitonin activates the PKA and PKC pathways, we investigated the contributions of PKA and PKC to IL-6 production. IL-6 production was only slightly increased by either 8-bromo-cAMP (1 mM) or phorbol 12-myristate 13-acetate (100 nM) alone. However, IL-6 was synergistically induced in the presence of both 8-bromo-cAMP (1 mM) and phorbol 12myristate 13-acetate (100 nM). Furthermore, calcitonin-induced IL-6 production was completely suppressed by H-89 (PKA inhibitor) or GF109203X (PKC inhibitor), indicating that the activation of both PKA and PKC is necessary for calcitonin-induced IL-6 production. On the other hand, pertussis toxin (G(i)/G(o) signaling inhibitor) treatment achieved an approximately 9-fold increase in calcitonin-induced IL-6 production. These results show that calcitonin-stimulated IL-6 production is mediated via both PKA- and PKC-signaling pathways, whereas calcitonin also suppresses IL-6 production by activating G(i)/G(o) proteins in folliculo-stellate cells.
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PMID:Calcitonin induces IL-6 production via both PKA and PKC pathways in the pituitary folliculo-stellate cell line. 1145 4

Calcitonin gene-related peptide (CGRP), is produced in dorsal root ganglia (DRG) neurons and released from primary afferent neurons to mediate hemodynamic effects and neurogenic inflammation. In this work, we determined whether lipopolysaccharide (LPS), an inflammatory stimulator, could trigger CGRP release from cultured DRG neurons and if so, which cellular signaling pathway was involved in this response. Cytoplasmic concentration of calcium ([Ca(2+)](i)) plays a key role in neurotransmitter release, therefore [Ca(2+)](i) was also determined in cultured DRG cells using fluo-3/AM. The results showed that LPS (0.1-10 microg/ml) evoked CGRP release in a time- and concentration-dependent manner from DRG neurons. LPS also increased [Ca(2+)](i) in a concentration-dependent manner. The protein kinase C (PKC) inhibitors, calphostin C 0.5 microM or RO-31-8220 0.1 microM, and the cAMP-dependent protein kinase (PKA) specific inhibitor RP-CAMPS 30 microM or nonspecific inhibitor H8 1 microM inhibited 1 microg/ml LPS-evoked CGRP release and [Ca(2+)](i) increase from DRG neurons. The cGMP-dependent protein kinase (PKG) inhibitor Rp-8-pCPT-cGMPS 30 microM did not block the LPS response. These data suggest that LPS may stimulate CGRP release and [Ca(2+)](i) elevation through PKC and PKA, but not PKG signaling pathway in DRG neurons of neonatal rats.
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PMID:PKC and PKA, but not PKG mediate LPS-induced CGRP release and [Ca(2+)](i) elevation in DRG neurons of neonatal rats. 1174 79

Calcitonin induces the association and tyrosine phosphorylation of focal adhesion kinase (FAK), paxillin, and HEF1 in HEK-293 cells that overexpress the calcitonin receptor (C1a-HEK), but the hormone's effect on these adhesion-related proteins in osteoclasts is not known. We therefore studied the effect of calcitonin on the tyrosine phosphorylation and subcellular distribution of paxillin, HEF1, FAK, and Pyk2, a FAK-related tyrosine kinase, in osteoclasts. Osteoclasts expressed both Pyk2 and FAK, with Pyk2 much more highly expressed. The two tyrosine kinases and paxillin were prominently associated with small punctate structures that were most densely clustered in the region of the peripheral F-actin-rich ring. Some of the punctate structures stained either for Pyk2 alone or FAK alone. Treatment with calcitonin disrupted the actin ring and induced the loss of the peripheral staining of paxillin, Pyk2, and FAK. In calcitonin-treated osteoclast-like cells, the tyrosine phosphorylation of paxillin and FAK increased, whereas the tyrosine phosphorylation of Pyk2 decreased. Calcitonin also induced increased phosphorylation of Erk1 and Erk2 in osteoclasts, as it did in the C1a-HEK cells. The unexpected dephosphorylation of Pyk2 correlated with decreased phosphorylation of Tyr(402), the autophosphorylation site of Pyk2. The calcitonin-induced dephosphorylation of Pyk2 was not observed in C1a-HEK cells transfected with Pyk2, suggesting that the reduced phosphorylation seen in osteoclasts may be specific to these cells. Treatment of osteoclast-like cells with 12-phorbol 13-myristate acetate increased the tyrosine phosphorylation of both Pyk2 and FAK, and calphostin C, an inhibitor of protein kinase C, blocked calcitonin-stimulated FAK phosphorylation. Increasing intracellular calcium with ionomycin caused a decrease in the tyrosine phosphorylation of Pyk2 and the loss of the actin ring in a manner similar to the effect of calcitonin. Ionomycin had no effect on FAK tyrosine phosphorylation. Calcitonin (CT)-induced changes in Pyk2, FAK, and Erk1/2 phosphorylation were independent of c-Src.
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PMID:Calcitonin induces dephosphorylation of Pyk2 and phosphorylation of focal adhesion kinase in osteoclasts. 1223 7

We investigated the neuronal locus, the role of PKC activation, and utilization of extracellular Ca(2+) and intracellular Ca(2+) release in smooth muscle cells for the generation of giant migrating contractions (GMCs) and rhythmic phasic contractions (RPCs) in intact normal and inflamed canine ileum. Calcitonin gene-related peptide (CGRP), administered close intra-arterially, stimulated GMCs at higher doses and RPCs at smaller doses. These effects were blocked by prior close intra-arterial infusions of CGRP(8-37), atropine, hexamethonium, and TTX but not by tachykinin, serotonin, and histaminergic receptor subtype antagonists. Both types of contractions were blocked by verapamil in normal and inflamed ileums. Dantrolene and ruthenium red blocked only the RPCs in normal ileum but blocked both GMCs and RPCs in the inflamed ileum. PKC inhibition by chelerythrine blocked GMCs only in inflamed ileum but blocked RPCs in both normal and inflamed ileums. The inhibition of phospholipase C by neomycin blocked both RPCs and GMCs in normal and inflamed ileums. In conclusion, acetylcholine is the common neurotransmitter for the stimulation of both GMCs and RPCs, but the signaling cascades for their stimulation are partially divergent, and they differ also in the normal and inflamed states.
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PMID:Neuronal locus and cellular signaling for stimulation of ileal giant migrating and phasic contractions. 1250 83

Although calcitonin is well known to be a potent inhibitor of bone resorption, it remains unknown how it regulates osteoclastic H(+) transport. In this study, we examined the effects of calcitonin on H(+) extrusion in cultured rat resorbing osteoclasts using an intracellular pH (pHi) indicator, BCECF [2'7'-bis-(2-carboxyethyl)- 5-carboxyfluorescein]. Resorbing osteoclasts were identified by their formation of resorbing pits on calcium phosphate-coated quartz coverslips. Both basal pHi and H(+) extrusion activity were significantly higher compared to non-resorbing osteoclasts. Two types of H(+)-extruding systems were identified by pharmacological and immunocytochemical means: a bafilomycin-A(1)-sensitive and an amiloride-sensitive system [H(+) extrusion mediated by a vacuolar type proton pump (V-ATPase) and by a Na(+)/H(+) exchanger (NHE), respectively]. Calcitonin inhibited both H(+) extrusion activities in a dose-dependent manner and this action was mimicked by protein kinase A (PKA) activators, but not by protein kinase C (PKC) activators. Pretreatment with PKA inhibitors completely suppressed calcitonin-induced inhibition, whereas neither PKC inhibitors nor calcium chelators suppressed it. These results indicate that calcitonin inhibits H(+) extrusion generated by V-ATPase and NHE via PKA activation. These inhibitory mechanisms of H(+) transport by calcitonin are important for the regulation of bone resorption.
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PMID:Calcitonin inhibits proton extrusion in resorbing rat osteoclasts via protein kinase A. 1263 84

Calcitonin gene-related peptide (CGRP) is synthesized in dorsal root ganglion (DRG) neurons and released from primary afferent neurons to mediate hemodynamic effects and neurogenic inflammation. The effect of the proinflammatory cytokine interleukin-1 (IL-1)-beta on CGRP release from these sensory neurons was investigated. The results showed that IL-1beta (1 ng/ml) could directly induce CGRP release following prolonged incubation (24 hr) with these neurons. Treatment with IL-1beta (0.1-1.0 ng/ml) significantly increased CGRP release in a concentration-dependent manner. In addition, pretreatment of DRG cells with actinomycin D at 1 microM or cyclohexamide at 10 microM for 30 min inhibited 1 ng/ml IL-1beta-induced CGRP release in DRG neurons of neonatal rats. The inhibitors of PKC, JNK MAPK and NF-kappaB, but not p38 or ERK1/2 MAPK, blocked IL-1beta-induced CGRP release. RNase protection assay showed that IL-1beta could cause alpha-CGRP mRNA increase in a time- and concentration-dependent manner, although the level of beta-CGRP mRNA was not affected. These results indicate that IL-1beta may activate PKC, which in turn initiates JNK MAPK and activates NF-kappaB and finally induces alpha-CGRP gene expression and release from these sensory neurons.
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PMID:Mechanism of interleukin-1 beta-induced calcitonin gene-related peptide production from dorsal root ganglion neurons of neonatal rats. 1283 61


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